Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists
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Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists. / Hansen, Martin; Phonekeo, Karina; Paine, James S; Leth-Petersen, Sebastian; Begtrup, Mikael; Bräuner-Osborne, Hans; Kristensen, Jesper Langgaard.
I: A C S Chemical Neuroscience, Bind 5, Nr. 3, 07.01.2014, s. 243-249.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Synthesis and structure-activity relationships of N-benzyl phenethylamines as 5-HT2A/2C agonists
AU - Hansen, Martin
AU - Phonekeo, Karina
AU - Paine, James S
AU - Leth-Petersen, Sebastian
AU - Begtrup, Mikael
AU - Bräuner-Osborne, Hans
AU - Kristensen, Jesper Langgaard
PY - 2014/1/7
Y1 - 2014/1/7
N2 - N-benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting sub-nanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1 to 40-fold) for the 5-HT2A receptor in the binding assays although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor.
AB - N-benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting sub-nanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1 to 40-fold) for the 5-HT2A receptor in the binding assays although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor.
U2 - 10.1021/cn400216u
DO - 10.1021/cn400216u
M3 - Journal article
C2 - 24397362
VL - 5
SP - 243
EP - 249
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 3
ER -
ID: 103038300